Here is the first group of abstracts from the ECTRIMS conference in Sweden this week which we can post:

These are the ones presented by doctors from BNAC (Zivadinov's team) and Ferrara (Zamboni's team)

They are the more "positive" in their findings, and I believe that is because BNAC is working with Zamboni's team to understand how to correctly utilize the technology to study CCSVI--

This first study finds a link to brain atrophy (shrinkage) and amount of lesions to presence of CCSVI:

Imaging 1

MRI results of blinded chronic cerebrospinal venous insufficiency study in patients with multiple sclerosis, healthy controls and patients with other neurologic diseases

R. Zivadinov, G. Cutter, K. Marr, M. Ramanathan, R.H.B. Benedict, M. Elfadil, N. Bergsland, C. Morgan, E. Carl, D. Hojnacki, E. Yeh, L. Willis, M. Cherneva, S. Hussein, J. Durfee, C. Kennedy, M. Dwyer, B. Weinstock-Guttman (Buffalo, Birmingham, US)

Background: Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular condition characterized by stenoses of the main extracranial veins with hampered cerebral venous outflow. Objective: To determine the relationship of CCSVI and conventional MRI outcomes in a large cohort of patients with multiple sclerosis (MS), clinically isolated syndrome (CIS), other neurological diseases (OND) and healthy controls (HC). Methods: A pre-planned examination of the first 499 consecutively enrolled subjects in the Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) blinded study included 289 MS, 163 HC, 26 OND and 21 CIS subjects. All subjects received extracranial and transcranial Doppler evaluation according to the proposed criteria (Zamboni et al., JNNP 2009). Of these, 20 (95.2%) CIS, 243 (84.1%) MS, 73 (45.6%) HC, and 15 (42.3%) OND received MRI examinations using a standardized protocol. In total, 351 (70.3%) of 499 subjects obtained MRI examination. T2, T1 and gadolinium (Gad) lesion number and volume (LV) were calculated. Normalized measures of global and central brain atrophy were also assessed. Differences in group means were assessed using the Kruskal-Wallis test and all correlations are reported using Kendall's tau. Results: The two venous scales' venous haemodynamic insufficiency severity score (VHISS) and number of venous haemodynamic criteria fulfilled (VH) were both significantly correlated with CCSVI diagnosis (Kendall's tau = .694 for VHISS, tau = .804 for VH, p < .001 for both scales). Subjects diagnosed with CCSVI (i.e. those who met at least 2 of the CCSVI criteria) had a significantly higher mean number of T2 lesions (x= 31.10, sd = 21.3, n = 173) than subjects classified as not having CCSVI (x= 24.96, sd = 22.7, n = 178; p < .001). Subjects diagnosed with CCSVI also had a significantly higher mean T2-LV (x= 20.69, sd = 8.9, n = 173) than those without CCSVI (x= 17.46, sd = 8.8, n = 173; p < .001). There was no significant difference between subjects with and without CCSVI for number orLV of either T1 or Gad lesions. Subjects diagnosed with CCSVI had significantly higher lateral ventricle volume (p < .001) than subjects without CCSVI. Subjects with CCSVI showed significantly lower gray matter volume (p = .023), brain parenchymal volume (p = .025) and cortical volume (p = .023) than subjects without CCSVI. Conclusions: Presence of CCSVI is significantly related to more severe lesion and brain atrophy MRI measures.

This next study is a genetic study looking at the frequency of HLA DR 1501 in CCSVI  (this is a human leukocyte antigen which is already known to be highly associated with MS)   This study is rather inconclusive regarding HLA DR and CCSVI, but once again, it shows the relationship between CCSVI and progressive MS....

Genetics/transcriptomics 1

Associations of HLA DR*1501 status and chronic cerebrospinal venous insufficiency in multiple sclerosis

B. Weinstock-Guttman, R. Zivadinov, G. Cutter, M. Tamano-Blanco, D. Badgett , K. Marr, E. Carl, M. Elfadil, C. Kennedy, M. Ramanathan (Buffalo, Birmingham, US)

Background: Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular condition characterized by anomalies of veins outside the skull (Zamboni et al, JNNP, 2009). The Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study was designed to independently confirm whether the presence of CCSVI was associated with multiple sclerosis (MS). Objectives: To evaluate the associations of HLA *1501 status and CCSVI correlates within the CTEVD study. Results: The CTEVD study enrolled 499 subjects: 163 healthy controls (HC), 289 MS patients, 21 clinically isolated syndrome patients (CIS), 26 controls with other neurological disorders (OND's). Genotyping was obtained for 472 of 499 subjects. All subjects underwent a clinical examination and a combined transcranial and extracranial Doppler scan of the head and neck. The HLA DR*1501 status was obtained by genotyping DNA from peripheral blood for rs3135005, a SNP strongly correlated with DR*1501 status. The controls group consisted of HC and OND's. The MS group was dichotomized into the non-progressive (relapsing remitting, CIS and Devic's disease) and progressive forms (secondary progressive and primary progressive). The frequency of CCSVI was higher (OR = 3.57, p < 0.001) in the MS group 54.8% vs. 25.4% in the controls group and also higher in the progressive MS group 69.6% vs. 48.6% in the non-progressive MS group. The frequency of HLA DR*1501 positivity (HLA+) in the MS group 49.5% was higher compared (OR = 2.15, p < 0.001) to 31.3% in the control group. The frequencies of HLA+ in the non-progressive and progressive MS groups were similar, 48.3% and 52.3% respectively. In the controls group, 53.1% were negative for both HLA DR*1501 and CCSVI (denoted HLA' CCSVI'), 22.3% were HLA+ CCSVI', 15.6% were HLA' CCSVI+ and 8.9% were HLA+ CCSVI+. In the non-progressive MS group, 27.1% were HLA' CCSVI', 23.7% were HLA+ CCSVI', 24.6% were HLA' CCSVI+ and 24.6% were HLA+ CCSVI+. In the progressive MS group, 18.6% were HLA' CCSVI', 11.6% were HLA+ CCSVI', 29.1% were HLA' CCSVI+ and 40.7% were HLA+ CCSVI+. Conclusions: These cross sectional data support an association between CCSVI and MS progression separate from HLA*DR1501. This association could imply that CCSVI is a risk factor for the progression of disease or that it is a consequence of the progression. Longitudinal studies need to be conducted to decipher the meaning and implications of this association

This is Dr. Zamboni's follow-up study in endovascular treatment of CCSVI in MS

Endovascular treatment for chronic cerebrospinal venous insufficiency in multiple sclerosis. A longitudinal pilot study

P. Zamboni, R. Galeotti, B. Weinstock-Guttman, G. Cutter, E. Menegatti, A.M. Malagoni, D. Hojnacki, M. Dwyer, N. Bergsland, M. Hiennen-Brown, A. Salter, C. Kennedy, I. Bartolomei, F. Salvi, R. Zamboni (Ferrara, IT; Buffalo, Birmingham, US; Bologna, IT)

Background: Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular picture characterized by multiple strictures at the level of the main extracranial cerebrospinal venous outflow routes that may interfere with normal venous drainage. Objective: To evaluate safety and tolerability of minimally invasive endovascular treatment (EVT) for CCSVI associated to MS using MRI, clinical and haemodynamic outcome measures. Methods: We designed an open-label, MRI-blinded, two-center, randomized, EVT intervention parallel-group, 12 month study (EVTMS). Of 16 relapsing-remitting patients who were screened for hemodynamic venous anomalies, 15 (8 from Italy and 7 from the Buffalo) accepted participation in the EVT intervention prospective study (EVTMS). Additional 8 age- and sex-matched healthy controls (HC), 4 from Italy and 4 from Buffalo were followed. All enrolled patients presented with CCSVI and were on disease-modifying therapy. Half of the cohort (immediate treatment group [IEVT], 4 from Buffalo and 4 from Italy) were randomly selected to obtain the EVT procedure (in Italy) immediately after the screening, and half (delayed treatment group [DEVT]) at 6 months. The EVT procedure consisted of selective venography complemented by balloon dilatation (PTA) when significant stenoses were detected. All patients were prospectively evaluated at 0, 3, 6, 9 and 12 months with sonography, MRI (0, 6 and 12 months only), and clinical examinations. Results: No serious adverse events occurred during the study except one transitory vaso-vagal syndrome approximately an hour after intervention.. One subject in DEVT group was lost from the study at 6 month follow-up. Three HC were lost to follow-up. Restenosis occurred in 29% of the study cohort after intervention (2 in DEVT arm at  3-month, 1 in the DEVT at 6-month and 1 in the IEVT arm at 12-month follow-up). There were no significant differences between the 2 groups at 6 months follow-up after the intervention for MRI and clinical outcomes. There was a significant decrease (p=0.0227) in T2 lesion number from the 6 month baseline time period to the 6 months following the intervention in DEVT arm. No significant worsening in mean change for other MRI and clinical metrics was observed in both groups over the follow-up. Conclusions: Treatment with PTA was safe and well tolerated. Rate of restenosis was low, 0% in the AZY and 29% in the IJV. Further and larger studies are needed to determine the effect of EVT for CCSVI in MS.

And here is Dr. Zivadinov's study on decreased grey matter in MS brains as associated with increased disability.  Once again, more proof that it's not about white matter lesions, it's about what is going on deep inside the brain---

Increased iron concentration and decreased volume of deep-grey matter are associated with increased disability in patients with multiple sclerosis

R. Zivadinov, M. Heininen-Brown, C. Schirda, N. Bergsland, C. Magnano, D. Hojnacki, D. Ramasamy, C. Kennedy, E. Carl, M. Dwyer, B. Weinstock-Guttman (Buffalo, US)

Background: MRI lesion-related measures account for only part of clinical disability in patients with multiple sclerosis (MS). New studies suggest that measurement of gray matter (GM) atrophy is clinically relevant, and is not entirely linked to white matter (WM) lesion formation. In particular, measurement of deep-gray matter (DGM) atrophy, which occurs from the earliest stages in the clinical course of MS, is under intense investigation. Objective: To investigate the relationship between iron concentration (IC), measured on susceptibility-weighted imaging (SWI), and volumes of the DGM with clinical outcomes in MS patients. Methods: Eighty-four (84) consecutive MS patients [58 relapsing-remitting (RR) and 26 secondary-progressive (SP]  were imaged on a 3T GE scanner using SWI. All patients were assessed with clinical and MRI outcomes. Disability was measured by Expanded Disability Status Scale (EDSS). Mean age in MS patients was 46.7 yrs, mean disease duration 14.6 yrs and median EDSS 2.5. High-iron tissue mean IC (HITMIC) was determined for the total DGM, caudate, putamen, globus pallidus, thalamus, pulvinar nucleus of the thalamus, hippocampus, amygdala, nucleus accumbens, red nucleus and substantia nigra. Volumes of the same DGM structures were calculated. T2, T1, Gadolinium (Gad) lesion volumes (LV) and global and central brain atrophy measures were also obtained. Results: Both increased IC (r=0.42, p<0.001) and decreased volume (r=0.31, p<0.01) of the total DGM were related to higher disability and longer disease duration. The relationship was stronger in SP compared to RR MS patients, particularly for IC measures. Of all examined DGM structures, caudate, putamen and thalamus showed the strongest correlations. In multivariate regression analysis, when all lesion, atrophy and IC measures that showed significant correlations in univariate analyses were entered, the only independent predictors of disability remained decreased total DGM IC (p=0.001) and increased T2-LV (p<0.001). Similar analysis selected normalized brain volume (p=0.006) for disease duration. Conclusions: Increased IC and decreased volume of DGM showed an important relationship to increased disability and longer disease duration. Measurement of IC and volume of DGM structures may become an important biomarker of disease progression in MS. Follow-up studies are needed to determine clinical relevance of the evolution of these MRI measures over mid-to long-term.

And here is another study looking at hypoperfusion in MS brains---literally, slowed blood flow--

Relation between quantitative venous vasculature assessment on susceptibility-weighted imaging and haemodynamic MRI metrics in multiple sclerosis patients

G. Poloni, M. Dwyer, F. Parker, C. Magnano, C. Schirda, N. Bergsland, R. Zivadinov (Buffalo, US)

Background: The venous vasculature of the brain parenchyma is significantly less visible on susceptibility-weighted         imaging (SWI) in patients with multiple sclerosis (MS) compared to healthy controls (HC), as previously described. Objective: To investigate the relation between the altered venous vasculature visibility in the brain parenchyma and  Cerebrospinal Fluid (CSF) Imaging and Perfusion Weighted Imaging (PWI) MRI metrics in patients with relapsing-remitting (RR) and secondary-progressive (SP) MS disease course, and HC. Methods: Fifty nine (59) MS patients [41 RR and 18 SP] and thirty three (33) age- and sex-matched HC were scanned on a 3T GE scanner using CSF imaging, PWI and SWI. Mean age at scan was 44.3 yrs, mean disease duration 13.2 yrs and median EDSS 2.5. CSF flow rates (positive, negative and net), Mean Transit Time (MTT), Cerebral Blood Flow (CBF) maps and Cerebral Blood Volume (CBV) maps were calculated. 3D multi-scale line filter was used to extract the venous vasculature from SWI images. Absolute venous volume (AVV) was estimated in milliliters (ml); relative venous intracranial fraction (VIF) was calculated to correct for head size and amount of brain atrophy. Vein volumes were classified by vein radius: <0.3mm, 0.3-0.6mm, 0.6-0.9mm and >0.9 mm. Voxel brain average distance-from-vein (DFV) maps were calculated. Results: MS patients showed reduced AVV, volume of veins with diameter <0.3mm and VIF (p< .05) and increased DFV (all p< .001) with respect to HC. In MS patients lower AVV, volume of veins with diameter <0.3mm and VIF, and higher DVF were strongly related to lower net negative flow (Spearman r = .48 to .61, p< .001) and higher net positive flow (r = .53 to .64, p< .001). A similar relation was found with an increased MTT (gray matter: r = .36 to .43, p< .01; white matter: r = .40 to .46, p< .001) and a decreased CBF (gray matter: r = .38 to .45, p< .01; white matter: r = .37 to .49, p< .001). The relationships were consistently stronger in RR than SP MS patients. No significances where found for HC. Conclusions: This study showed that lower brain parenchyma venous vasculature visibility on SWI is related to altered hemodynamic CSF flow and hypoperfusion in patients with MS. The events contributing to these findings are probably occurring early in the disease process. Further studies are needed to elucidate relationship between reduction of venous vasculature and the hemodynamic MRI parameters in MS patients.